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Elzbieta Kaczmarek, PhD

Assistant Professor in Surgery
Beth Israel Deaconess Medical Center
Harvard Medical School

330 Brookline Avenue, RN 370E
Boston, MA 02215

Office: 617-667-1677
Fax: 617-667-0445
Email: ekaczmar@bidmc.harvard.edu

Education/Training/Appointments

Elzbieta Kaczmarek earned a M.Sc. in Molecular Biology from Warsaw University in Warsaw, Poland and later a Ph.D. in Biochemistry from Jagiellonian University in Cracow, Poland in 1985. She performed a post-doctoral study at Beth Israel Hospital in Boston. In 1995 she joined the Immunobiology Center at Beth Israel Deaconess Medical Center and became a member of the CVBR in 2008.

Research Interests

P2 receptor signaling in endothelial cells

Basic Research

For the last nine years my research has been focused on the P2 receptor signaling in endothelial cells (EC). Nucleotides are released into extracellular fluids and blood as result of cell death, exocytosis of nucleotide-containing granules and/or efflux through a membrane transport system in response to cell activation. Extracellular nucleotides function as paracrine or autocrine mediators via activation of their respective purinergic P2 receptors, classified into two groups: P2X, ligand-gated ion channels, and P2Y, G protein-coupled receptors. Most cells, including EC, express multiple P2 receptor subtypes. Activation of P2 receptors by extracellular nucleotides initiates several signaling pathways, which regulate activation and expression of various proteins and affect many physiologic cell functions, such as cell migration, proliferation and apoptosis. Our long-term plan is to investigate purinergic mechanisms in EC in the context of diabetic complications.

Purinergic Activation of eNOS and Its Possible Consequences

We have recently shown that extracellular nucleotides, acting via P2Y receptors, activate eNOS in EC. This newly identified eNOS activation pathway, contrary to VEGF, is not inhibited by high glucose. Therefore, extracellular nucleotide-induced generation of nitric oxide may be beneficial in protecting the endothelium from dysfunction linked to diabetes mellitus. We are investigating the molecular mechanism(s) of this observation, possibly associated with inhibition by P2 receptor signaling of high glucose-induced reactive oxygen species (ROS) formation, PKC Beta II activation and eNOS O-glycosylation.

Purinergic Activation of AMP-activated Protein Kinase (AMPK), a Key Energy Sensor and Regulator in the Cells

We identified in EC two new pathways of AMPK activation via extracellular nucleotides and adenosine. We investigate effects of P2 receptor signaling on AMPK-related energy regulation and glucose and fatty acid metabolism. Moreover, we examine the role of AMPK in extracellular nucleotide-induced EC proliferation and protection from high glucose-mediated apoptosis.

New and Noteworthy Publications

View all publications via PubMed >>

  1. Kaczmarek E, Koziak K, Sévigny J, Siegel JB, Anrather J, Beaudoin AR, Bach FH, Robson SC (1996) Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem 271:33116-22. In this study we identified CD39 as the main vascular ecto-NTPDase. We further demonstrated that ATPDase could inhibit platelet aggregation in response to ADP, collagen, and thrombin. This paper initiated multiple studies on CD39 structure and function.

  2. Kaczmarek E. Erb L, Koziak K, Jarzyna R, Wink MR, Guckelberger O, Blusztajn JK, Trinkaus-Randall V, Weisman GA, Robson SC. (2005) Modulation of endothelial cell migration by extracellular nucleotides. Involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways. Thromb Haemost. 93:735-42. In this study we showed that stimulation of EC with ATP or UTP increased intracellular free calcium ion concentrations, induced phosphorylation of focal adhesion kinase (FAK), p130cas and paxillin, and caused cytoskeletal rearrangements with consequent cell migration.

  3. Silva C, Jarzyna R, Specht A, Kaczmarek E. (2006) Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells. Involvement of P2 receptors and adenosine transporters. Circ Res 98:e39-47. In this study we demonstrated that in EC extracellular nucleotides (ATP, UTP and ADP) activate AMP-activated protein kinase (AMPK) via an increase in concentration of intracellular Ca2+ and by Ca2+/calmodulin-dependent kinase kinase (CaMKK). In addition, we showed that adenosine, originating from hydrolyzed ATP or ADP, induces AMPK activation in EC via activation of LKB1. P2 receptor signaling may regulate in EC energy homeostasis, secondary to AMPK activation.

  4. Koziak K, Bojakowska M, Robson SC, Bojakowski K, Soin J, Csizmadia E, Religa P, Gaciong Z, Kaczmarek E. (2008) Overexpression of CD39/nucleoside triphosphate diphosphohydrolase-1 decreases smooth muscle cell proliferation and prevents neointima formation after angioplasty. J Thromb Haemost 6:1191-7. This study shows that overexpression of CD39/NTPDase1 (an enzyme hydrolyzing extracellular nucleotides) by the recombinant adenoviral gene transfer into vascular smooth muscle cells of aorta, following balloon endothelial denudation, significantly reduced smooth muscle cell proliferation and neointima formation. These results indicate that P2 receptor signaling plays an important role in neointima formation after angioplasty.

  5. Silva C, Specht A, Wegiel B, Ferran C, Kaczmarek E. (2009) Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cells. Circulation (February 2). In this study we elucidated the mechanism of eNOS activation by extracellular nucleotides. We showed that ATP, UTP and ADP phosphorylate eNOS at Ser-1177 and induce NO generation via pathway dependent on Ca2+ and PKC&. Purinergic activation of eNOS may protect the endothelium from dysfunction, such as observed in diabetes or hypertension.

Contact Information

Nicole Magner, Administrative Assistant
Center for Vascular Biology Research
Beth Israel Deaconess Medical Center
Research North
99 Brookline Avenue
Boston, MA 02215
617-667-0654
info.cvbr@bidmc.harvard.edu